|
q
The following is derived from a
lecture I gave in Oct 2002 intended for the teaching of mental health
professionals. It is a combination of the author's views and published
guidelines based on best practice principles derived from studies and expert
opinions.
The author takes no responsibility for the accuracy or degree of updatedness of
the information below. This information is intended for education purposes by mental health professionals and
should not be used as a substitute for any health professionals' individual
advice and treatment. Every patient needs to be treated as an individual
and individual requirements may differ from general guidelines or principles
like those suggested below.
Contents
General
management
principles for treatment of psychotic disorders
Principles
for medication use in first-episode psychosis
Goals
of medication use in first-episode
psychosis
If
possible employ a neuroleptic free observation period of 48 hrs +
Low-dose atypical neuroleptics are first line treatments
Advantages
of typical antipsychotics
Advantages
of atypical antipsychotics
Oral
route is preferred in both acute & maintenance phases
Most
first episode pts will respond to very low doses of medication
Use
a ‘START LOW/GO SLOW’ approach
Depressed
mood in first-episode psychosis
Use
of mood stabilisers in first-episode psychosis
Aim
for remission not adjustment
How
long to treat?
Some
patients with schizophrenia may require <2 yrs treatment
Non-schizophrenia
first-episode?
Possible
Diagnoses
Choosing
the antipsychotic
Where
to treat?
Why
admit?
Setting
issues
Characteristics
of atypical antipsychotics
Clozapine
(Clozaril) Profile
When
clozapine is used
Risperidone
(Risperdal) Profile
When
risperidone is used
Olanzapine
(Zyprexa) Profile
When
olanzapine is used
Quetiapine
(Seroquel) Profile
When
quetiapine is used
Amisulpride
(Solian) profile
When
amisulpride is used
Summary
Acknowledgements
General
management
principles for treatment of psychotic disorders
 | Antipsychotic
medication is the cornerstone of treatment for the majority of
patients (occasionally,
other treatments alone are sufficient e.g. reduction of sensory impairment,
effective treatment of an underlying general medical condition or underlying
non-psychotic mental disorder that is fuelling the psychotic symptoms, psychotherapy
- especially in personality disordered or substance abusing patients) |
| qThe treatment of psychotic disorders often requires a team approach
(sometimes
a patient cannot tolerate the stimulation of more than one mental
health professional or choose against a multidisciplinary team in the early
stages or if their symptoms fully remit with treatment) |
| qPsychosocial
interventions should be provided by trained mental health professionals with
time / resources to implement them, including:
 | uPsychoeducation |
| uuTreatment of comorbid physical & mental disorders |
| Psychosocial interventions (if
resources are available) |
|
Principles
for medication use in first-episode psychosis
| Pharmacological
interventions need to be used in acute & maintenance phases. |
|  Treatment
should be provided in the least restrictive & stigmatised setting. |
| Management
should include low-dose, preferably atypical antipsychotics & CBT
(cognitive behaviour therapy). |
Goals
of medication use in first-episode
psychosis
|  To
maximise the therapeutic benefit whilst minimising side effects |
| To
ensure the experience is as positive as possible |
| To
adequately treat the psychotic symptoms, considering issues of long-term
compliance & respecting the client’s legitimate aspirations of
autonomy |
If
possible employ a neuroleptic free observation period of 48 hrs +
| lDiagnosis
of psychosis can be confirmed & general medical causes excluded |
| lDiagnosis
of psychosis often difficult |
| lPossibly
only chance to observe patient without meds |
| lParticularly
helpful in presence of heavy substance use |
| lBenzodiazepines
can be used for sedation |
Low-dose atypical neuroleptics are first line treatments
| Most
evidence with risperidone & olanzapine |
| lBetter
tolerated |
| lAssociated
with less:
| Extra-pyramidal
SE’s (EPSE's) |
| Cognitive
impairment |
| Tardive dyskinesia (TD) |
|
Advantages
of typical antipsychotics
e.g. chlorpromazine, haloperidol, trifluoperazine, fluphenazine
|
nFamiliar
|
| nKnown
mechanism: dopamine receptor blockade
|
| nEffective
for positive symptoms
|
| nInexpensive
|
| nMany
patients stabilised on them
|
| nAvailable
in many formulations
|
Advantages
of atypical antipsychotics
| More
effective for:
| ünegative |
| ücognitive |
| affective? |
| positive
symptoms?? |
|
| ??nReduced
EPSE & TD
|
| Reduced risk of
prolactin elevation & NMS (malignant neuroleptic syndrome)
|
| nImproved
neurophysiological profile (as seen on positron emission tomography {PET}
and magnetic resonance imaging {MRI} wrt basal ganglia size)
|
| First-
line in western world
|
Why atypicals have less EPS, TD, NMS
and
lower prolactin elevations:
| nThey
block post-synaptic dopamine receptors like typicals
|
| They
block pre-synaptic 5HT2a receptors, causing more dopamine release
(disinhibition)
|
| Outcome:
reduced net dopamine blockade in serotonin-dopamine antagonism in nigrostriatal & infundibular pathways |
PET
scan of conventional vs atypical D2 binding
Why are atypicals better at reducing
negative and cognitive symptoms?
Selective increase in dopamine may reverse hypofrontality in 5HT2A-D2 antagonism in the mesocortical pathways
PET
scan of typical vs atypical 5HT2A binding
 (reversed hypofrontality on right
scan)
Oral
route is preferred in both acute & maintenance phases
|  Depot
medication should only be used after oral meds, psychoeducation &
compliance therapies have been trialed |
| Rooke
& Birchwood (1998) found that entrapment was the biggest predictor of
depression in 49 patients with established schizophrenia |
Most
first episode pts will respond to very low doses of medication
| McGorry
(1999) found that mean dose for initial 10 weeks = RIS 2.8 mg/d |
| q65%
of pts respond over 2-3 wks to RIS 2 mg or OLZ 10 mg/d |
| qKontaxakis
(2000) found 76% responded to RIS 3 mg/d or less |
| qSanger
(1999) found mean endpoint dose of OZP used in 1st episode pts = 11.6
mg/d |
Use
a ‘START LOW/GO SLOW’ approach
| Pts
may take 2-4 weeks to begin to respond |
|  Doses
may not need to be greater than RIS 2 mg/day or OZP 10 mg within the
first 3 weeks of treatment |
| If
response is inadequate, cautious increases as tolerated are warranted, but
little evidence to support > 6 mg/day haloperidol equivalent doses (e.g. Remmington et al 1998) |
Why?
| Fast
titration or high doses are not necessarily more effective (e.g. McEvoy
1991) |
| qPET
studies show 50-70% D2-blockade at low dose (e.g. Kapur et al 1996) |
| qMay
avoid transient SE’s |
| First-episode patients have better response ? |
| qHigh
D2 blockade may increase depressive symptoms |
Depressed
mood in first-episode
psychosis
| In
most cases depressed mood will resolve with the psychosis (Koreen et al
1993) |
|  Reserve
antidepressants for cases where depression clearly precedes psychosis or
fails to resolve
(Australian Clinical
Guidelines) |
Use
of mood stabilisers in first- episode
psychosis
| Should
be added in presence of clear mood symptoms (mania, hypomania, rapid
cycling) that fails to respond to antipsychotic meds alone
(Australian Clinical
Guidelines, NEPP 1998) |
|  McGorry
(1994, 95) advocates a ‘symptomatic approach’ |
| Consider
sodium valproate > lithium > carbamazepine > lamotrigine |
Aim
for remission not adjustment
| Assertive
treatment leads to remission in the vast majority of pts with first- episode
psychosis |
|  Lieberman
et al (1993) found 74% fully remitted in 1 year (& 83% had no more
than mild positive symptoms) |
How
long to treat?
| Current
guidelines suggest ceasing meds after 1-2 years of remission in those with
schizophrenia (likely to be changed to 2-5 years) |
|  Robinson
et al (1999): 2 year relapse rate = 78%; 5 year RR = 81.9% |
| Wiersma
et al (1998): 5 year RR = 70% |
Some
patients with schizophrenia may require <2 yrs treatment
| Predicting
who they are is difficult |
|  Consider
reducing med dose 6-9 months after full clinical remission (continue
monitoring) |
| Greatest
predictor of relapse is DUP > 1 year (Crow et al 1986); 30% on placebo
did not relapse x 2 yrs after treatment of first-episode |
| Risk
of relapse disappeared by 9 years (Wiersma et al 1998) |
Non-schizophrenia
first-episode?
EPPIC
Practice:
Non-affective
psychosis
lBrief
episode / good prognosis:
6-9 months
lLonger
episode / poorer prognosis: 1-2 yrs
lAffective
psychosis
Manic
episode: Cease when positive symptoms abate (lithium for 9 months)
MDD:
4-6 weeks (Antidepressant: for 6-12 months)
Possible
Diagnoses
| Schizophrenia
/ Schizophreniform disorder |
|  Delusional
disorder |
| Drug-induced
psychosis |
| Schizoaffective
disorder |
| BPAD
- both phases |
| Major
depression with psychotic features |
| Personality
disorder / Brief-reactive psychosis |
| Anxiety
disorders e.g. PTSD, OCD |
| Dementia
/ delirium / brain injury / mental retardation |
Choosing
the antipsychotic
| Efficacy |
| lFor
specific symptom profile |
| lFor
mental disorder (diagnosis) |
|  Side
effect profile |
| lBenefits
to that pt |
| lDisadvantages
to that pt |
| Continuing
the antipsychotic already commenced by referring or admitting doctor
(completing the trial) |
|  Experience
Local practice |
| Economic |
| lLocal
restrictions |
| lCost
to taxpayer |
| Consider
symptom clusters |
Where
to treat?
| The emergency department |
|  The psychiatric admissions unit |
| The acute adult psychiatric ward |
| The private psychiatric hospital ward |
| The community health centre |
| The private consulting room |
| The
general practice |
| The
nursing home |
Why
admit?
Sanctuary
| Removal
from noxious environment
|
| Negative
stimuli
|
| High
EE interactions
|
| lHomelessness
/
isolation
|
| Substance
abuse
|
Healing factors
| lPositive
stimuli
|
| Network
of therapeutic relationships e.g. group milieu
|
| Therapeutic
responses from clinical staff
|
| lReduction
of stimuli
|
 Containment
| Risk to self / others |
| lRisk to reputation |
| lVulnerability
to exploitation |
| lOverwhelming
emotions & confusion (disintegration) |
l
Holding
tank for meds to kick in?
| l"The
right drug, in the right patient, at the right dose" |
Setting
issues
| Patient
referral experiences |
|  Hospital
characteristics
| lLocation
/ structure / mainstreamed / standalone |
| lHospital
aesthetics e.g. age, era, upkeep |
| lContinuity
of treating staff |
|
| Prevailing
local ideology
e.g. holding tank vs therapeutic
environment |
| Politics
| lPressure
on length of stay |
| lDiagnostic
Filters e.g. DRG |
| lNo.
of acute / ultra-acute / rehab / D&A beds |
| System
resources e.g. community vs inpatient |
|
| Multidisciplinary
team characteristics
| Staff
training / expertise / skills |
| Staff
mix & cohesion |
|
| ll Ward
programs & activities |
| Nature
of other patients |
| lDiagnostic
profile of patient mix |
| lPublic
/ Private |
| lLegal
status |
Clozapine
(Clozaril) Profile
| Most
efficacious for positive &
negative symptoms, TD, treatment resistance, suicidality, aggression |
| nMost
dangerous: agranulocytosis 0.5-2%, seizures & myocarditis |
| nOther
SE's: Weight gain, sialorrhoea (dribbling), sedation, diabetes, rebound psychosis |
| nMost
hassle: needs regular full blood count & cardiac monitoring, usually hospitalisation
necessary |
When
clozapine is used
| Treatment resistant schizophrenia |
| uProminent negative / cognitive symptoms |
| uHigh risk of suicide & aggression |
| uStable accommodation & compliance |
| uTardive dyskinesia |
| Purevious malignant neuroleptic syndrome Comorbid Parkinson’s
disease |
| uComorbid Lewy-body dementia |
Risperidone
(Risperdal) Profile
| nLow
doses often adequate |
| nNo
anticholinergic activity: good in youth, organicity & elderly |
| nDose-related
Ýprolactin
(may cause impotency & galactorrhoea) & EPSE |
| nLow
sedation: may need benzo adjunct in acute agitation, nurses often use
excessive PRN typicals |
| n‘Scalpel’
dosing |
| nAim
for 2-5 mg, avg=3.5 mg |
| nSyrup
available |
When
risperidone is used
| uFirst onset psychosis |
| uFirst trial of atypical |
| uLong-term relapse prevention |
| uElderly |
| uYouth |
| uComorbid Alzheimer’s dementia |
| uRisk of drug interactions |
Olanzapine
(Zyprexa) Profile
| nEPS
unusual |
| nGood
for mood symptoms |
| nPleasant
sedative effect acutely |
| nHigh
risk of weight gain |
| nIncreasing
concern of ßgluc tol, DM &
DKA |
| nNarrower
dosage range 5-20 mg (easy titration) |
| nWafer
available |
When
olanzapine is used
| nManic, drug-induced, agitated & depressive psychoses |
| uWhen need simple regime |
| uMood stabilisation |
| uAdjunct in melancholic depression |
| uAdjunct to depot |
| uPrevious malignant neuroleptic syndrome |
| uFailed earlier antipsychotic trial |
Quetiapine
(Seroquel) Profile
| nLow
EPS & Ý
prolactin |
| nGood
for mood symptoms |
| nLow
weight gain |
| nSedation
the main SE |
| nRare
pt sensitive to anticholinergic SE's |
| nDose
v. variable: |
| First-onset schizophrenia: 400-700 mg |
| nTreatment
Resistant schizophrenia:
700-1200+ mg |
| nBPAD:
100-400 mg |
| nMelancholic
MDD:
25-200 mg |
| nHard
to determine optimal dose when switching to it |
| nTwice
daily regime |
When
quetiapine is used
| Second line |
| uTreatment resistant schizophrenia |
| uWhere weight is a cause for concern |
| uMood stabilisation |
| uSedation required |
| uAdjunct in melancholic / psychotic depression |
| uAdjunct to clozapine (treatment resistant resistant schizophrenia) |
| uTardive dyskinesia |
Amisulpride
(Solian) profile
| Low
EPS, sedation, wt gain, prolactin, anticholinergic SEs |
|  Lower
doses (50-300 mg) for negative symptoms & depression (Blocks presynaptic dopamine auto-receptors in frontal cortex ) |
| Higher
doses for positive symptoms (400-800 mg) (Blocks
postsynaptic dopamine receptors in limbic cortex) |
| Treatment
resistant pts may need up to 1200 mg/d |
When
amisulpride is used
| Prominent negative symptoms |
| uWhere weight is a cause for concern |
| uTreatment resistant schizophrenia |
| uSecond line? |
| uTardive dyskinesia? |
| uNMS? |
| uAvoiding Ý
prolactin
SE’s? |
| uAVOID in bipolar disorder type I / schizomania?? |
| uComorbid or standalone dysthymia |
| uTreatment resistant MDD? |
Summary
|  A
neuroleptic-free observation period can be helpful |
| Start
low / go slow |
| Use
benzodiazepines for sedation |
| Symptomatic
approach is OK |
| Often
don’t get Rx or Dx right first |
| Uncertainty
& variability wrt when & if to cease Rx |
| Don’t
take anyone with a DUP>1 yr off medication in <2 yrs |
Pictures & Diagrams adapted from:
Psychopharmacology
of Antipsychotics
by Stephen
M. Stahl
Paperback : 160 pages
Publisher : Martin Dunitz Ltd; ISBN: 185317601X; 1st edition (June 17, 1999)
Sources of guidelines for medication in first episode
psychosis:
AUSTRALIAN
CLINICAL GUIDELINE 3.5
INITIATIVE
TO REDUCE THE IMPACT OF CLINICAL GUIDELINES AND SERVICE
FRAMEWORKS
Guiding
principle 4
Guideline
4
NORTHERN
SYDNEY HEALTH AREA MENTAL HEALTH CONSENSUS GUIDELINES
APA
1997
WORKING
GROUP FOR THE CANADIAN PSYCHIATRIC ASSOCIATION AND THE CANADIAN ALLIANCE FOR
RESEARCH ON SCHIZOPHRENIA, 1998
BETHLEM
AND MAUDSLEY NHS TRUST, 1999
EXPERT
CONSENSUS PANEL, 1999
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Citation suggestion: Dr Gary Galambos, Medication Use in First Onset Psychosis
Lecture (http://www.ep.org.au/gg/lecs/psychosis.htm) [date accessed]
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